A sobrecarga crônica com frutose induz alterações vasculares que envolvem a redução do relaxamento dependente do endotélio (EL-BASSOSSY; DSOKEY; FAHMY, 2014; NYBY et al., 2007; ROMANKO et al., 2009; TAKAGAWA et al., 2001), e aumento da contração (EL-BASSOSSY; DSOKEY; FAHMY, 2014; ROMANKO et al., 2009). O exato mecanismo pelo qual o consumo de frutose leva a esses efeitos ainda não foi elucidado mas alguns artigos têm associado ao aumento da produção de EROs (NYBY et al., 2007; ROMANKO et al., 2009), de prostanóides vasoconstritores (PUYÓ et al., 2009), da ação da angiotensina II (NYBY et al., 2007) e da ação da endotelina (JUAN et al., 1998) sobre o músculo liso vascular. Todos esses estudos também observaram alterações metabólicas como aumento dos níveis de insulina e triglicerídeos no sangue, além de aumento da pressão arterial, que podem contribuir para a disfunção vascular. Assim, não é possível separar os efeitos diretos da frutose dos efeitos decorrentes de seu metabolismo. Nossos resultados mostram claramente que a frutose exerce um efeito direto sobre os vasos sanguíneos, causando disfunção endotelial. Além disso, os efeitos observados após exposição in
vitro à frutose guardam semelhanças com os efeitos vasculares induzidos pela dieta crônica com frutose.
6. CONCLUSÃO
Os efeitos da dieta com alta frutose sobre o sistema cardiovascular têm sido estudados em modelos animais e humanos (EL-BASSOSSY; DSOKEY; FAHMY, 2014; JALAL et al., 2010; MADERO et al., 2011; SLYPER, 2013). Entretanto, muitos desses estudos relacionam as alterações vasculares com outros efeitos decorrentes do metabolismo da frutose, como hiperuricemia (NAKAGAWA et al., 2006), hipertrigliceridemia, hiperinsulinemia e hiperglicemia (EL-BASSOSSY; DSOKEY; FAHMY, 2014; TAKAGAWA et al., 2001).
Nossos resultados demonstraram que a exposição aguda à frutose induz aumento do estresse oxidativo via ativação excessiva da NADPH oxidase, o que aumenta a produção de ânion superóxido e, consequentemente, a degradação de NO, culminando em aumento da reatividade à fenilefrina e redução do relaxamento induzido pela acetilcolina. Além disso, o aumento da reatividade vascular à fenilefrina e redução do relaxamento à acetilcolina é influenciada pelo peróxido de hidrogênio (Figura 20). Assim, o desequilíbrio de agentes vasoativos, em especial as espécies reativas de oxigênio, pode ser o mecanismo chave pelo qual a frutose induz respostas vasoconstritoras agudas e pode explicar as alterações vasculares observadas após a ingestão de frutose. Nosso estudo apresenta fortes evidências de que a frutose afeta diretamente os vasos sanguíneos, causando disfunção vascular.
Figura 20. Resumo gráfico dos efeitos da exposição in vitro à frutose sobre a reatividade vascular de
7. REFERÊNCIAS
ADMIRAAL, P. J. et al. Metabolism and production of angiotensin I in different vascular beds in subjects with hypertension. Hypertension, v. 15, n. 1, p. 44–55, 1990.
ASSY, N. et al. Soft drink consumption linked with fatty liver in the absence of traditional risk factors. Canadian journal of gastroenterology = Journal canadien de gastroenterologie, v. 22, n. 10, p. 811–6, out. 2008.
BALLINGER, S. W. et al. Mitochondrial integrity and function in atherogenesis. Circulation, v. 106, n. 5, p. 544–9, 30 jul. 2002.
BERTOLUCI, M. et al. Endothelial dysfunction as a predictor of cardiovascular disease in type 1 diabetes. World Journal of Diabetes2015, v. 6, n. 5, p. 679–692, 2015. BISMUT, H.; HERS, H. G.; VAN SCHAFTINGEN, E. Conversion of fructose to glucose in the rabbit small intestine. A reappraisal of the direct pathway. European journal of biochemistry, v. 213, n. 2, p. 721–6, 15 abr. 1993.
BRAY, G. A.; NIELSEN, S. J.; POPKIN, B. M. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesityAmerican Journal of Clinical Nutrition, 2004.
BROWN, C. M. et al. Fructose ingestion acutely elevates blood pressure in healthy young humans. American journal of physiology. Regulatory, integrative and comparative physiology, v. 294, p. 730–737, 2008.
CAI, H. Hydrogen peroxide regulation of endothelial function: Origins, mechanisms, and consequences. Cardiovascular Research, v. 68, n. 1, p. 26–36, 1 out. 2005. CHICCO, A. et al. Multiphasic Metabolic Changes in the Heart of Rats Fed a Sucrose- Rich Diet. Hormone and Metabolic Research, v. 26, n. 9, p. 397–403, 14 set. 1994. COHEN, R.; ADACHI, T. Nitric-Oxide-Induced Vasodilatation: Regulation by Physiologic S-Glutathiolation and Pathologic Oxidation of the Sarcoplasmic Endoplasmic Reticulum Calcium ATPase. Trends in Cardiovascular Medicine, v. 16, n. 4, p. 109–114, maio 2006.
COSTEROUSSE, O. et al. [Angiotensin converting enzyme (kininase II). Molecular and physiological aspects]. Comptes rendus des seances de la Societe de biologie et
de ses filiales, v. 186, n. 6, p. 586–98, 1992.
DAI, S.; MCNEILL, J. H. Fructose-induced hypertension in rats is concentration- and duration-dependent. Journal of Pharmacological and Toxicological Methods, v. 33, n. 2, p. 101–107, 1995.
DELBOSC, S. et al. Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat. Atherosclerosis, v. 179, n. 1, p. 43–49, 2005.
DORNAS, W. C. et al. Health Implications of High-Fructose Intake. v. 1, p. 729–737, 2015.
DOROUDI, R. et al. Effects of shear stress on eicosanoid gene expression and metabolite production in vascular endothelium as studied in a novel biomechanical perfusion model. Biochemical and biophysical research communications, v. 269, n. 1, p. 257–64, 5 mar. 2000.
DOUARD, V.; FERRARIS, R. P. The role of fructose transporters in diseases linked to excessive fructose intake. The Journal of physiology, v. 591, n. Pt 2, p. 401–14, 2013.
EL-BASSOSSY, H. M.; DSOKEY, N.; FAHMY, A. Characterization of vascular complications in experimental model of fructose-induced metabolic syndrome. Toxicology mechanisms and methods, v. 0, n. 0, p. 1–8, 2014.
EMMERSON, B. T. Effect of oral fructose on urate production. Ann. rheuim. Dis, v. 33, p. 276–280, 1974.
ENDO, M. Y. et al. Acute responses of regional vascular conductance to oral ingestion of fructose in healthy young humans. Journal of physiological anthropology, v. 33, n. 1, p. 11, 17 maio 2014.
FEINMAN, R. D.; FINE, E. J. Fructose in perspective. Nutrition & Metabolism, v. 10, p. 1, 2013.
FÉLÉTOU, M.; HUANG, Y.; VANHOUTTE, P. M. Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. British Journal of Pharmacology, v. 164, n. 3, p. 894–912, 2011.
England : 1979), v. 117, n. 4, p. 139–155, 2009.
FOX, I. H.; KELLEY, W. N. Studies on the mechanism of fructose-induced hyperuricemia in man. Metabolism, v. 21, n. 8, p. 713–721, 1972.
FRÖLICH, J. C.; FÖRSTERMANN, U. Role of eicosanoids in regulation of vascular resistance. Advances in prostaglandin, thromboxane, and leukotriene research, v. 19, p. 211–5, 1989.
FUNK, C. D.; FITZGERALD, G. A. COX-2 Inhibitors and Cardiovascular Risk. Journal of Cardiovascular Pharmacology, v. 50, n. 5, p. 470–479, nov. 2007.
FURCHGOTT, R. F. Role of Endothelium in Responses of Vascular Smooth Muscle. Circulation Research NOVEMBER An Official Journal of the American Heart Atmooia, v. 53, n. 5, p. 557–73, 1983.
GBD 2013 MORTALITY AND CAUSES OF DEATH COLLABORATORS, I. FOR H. M. AND et al. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet (London, England), v. 385, n. 9963, p. 117– 71, 10 jan. 2015.
GRIENDLING, K. K.; SORESCU, D.; USHIO-FUKAI, M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circulation research, v. 86, n. 5, p. 494–501, 17 mar. 2000.
HANOVER, L. M.; WHITE, J. S. Manufacturing, composition, and applications of fructose. American Journal of Clinical Nutrition, v. 58, n. 5 SUPPL., 1993.
HUI, H. et al. Direct spectrophotometric determination of serum fructose in pancreatic cancer patients. Pancreas, v. 38, n. 6, p. 706–12, ago. 2009.
HWANG, I. S. et al. Fructose-induced insulin resistance and hypertension in rats. Hypertension (Dallas, Tex. : 1979), v. 10, n. 5, p. 512–6, nov. 1987.
ISHIMOTO, T. et al. Opposing effects of fructokinase C and A isoforms on fructose- induced metabolic syndrome in mice. Proceedings of the National Academy of Sciences, v. 109, n. 11, p. 4320–4325, 13 mar. 2012.
JALAL, D. I. et al. Increased Fructose Associates with Elevated Blood Pressure. p. 1543–1549, 2010.
JUAN, C. et al. Overexpression of vascular endothelin-1 and endothelin-A receptors in a fructose-induced hypertensive rat model. v. 1, p. 1775–1782, 1998.
KASSAB, A.; PIWOWAR, A. Cell oxidant stress delivery and cell dysfunction onset in type 2 diabetes. Biochimie, v. 94, n. 9, p. 1837–1848, set. 2012.
KLEIN, A. V; KIAT, H. The mechanisms underlying fructose-induced hypertension: a review. J. Hypertens., v. 33, n. 5, p. 912–920, 2015.
KOEPPEN, B. Berne e Levy Fisiologia. 6a. ed. [s.l.] Elsevier Brasil, 2011.
KURTZ, T. W. et al. Liquid-chromatographic measurements of inosine, hypoxanthine, and xanthine in studies of fructose-induced degradation of adenine nucleotides in humans and rats. Clinical Chemistry, v. 32, n. 5, p. 782–786, 1986.
LE, K.-A. et al. Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes. American Journal of Clinical Nutrition, v. 89, n. 6, p. 1760–1765, 1 jun. 2009. LÊ, K.-A. et al. A 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humans. The American journal of clinical nutrition, v. 84, n. 6, p. 1374–9, dez. 2006.
LI, W. G. et al. H(2)O(2)-induced O(2) production by a non-phagocytic NAD(P)H oxidase causes oxidant injury. The Journal of biological chemistry, v. 276, n. 31, p. 29251–6, 3 ago. 2001.
LOPERENA, R.; HARRISON, D. G. Oxidative Stress and Hypertensive Diseases. Medical Clinics of North America, v. 101, n. 1, p. 169–193, jan. 2017.
MADERO, M. et al. Dietary fructose and hypertension. Current Hypertension Reports, v. 13, n. 1, p. 29–35, 2011.
MARDINI, I. A.; FITZGERALD, G. A. Selective inhibitors of cyclooxygenase-2: a growing class of anti-inflammatory drugs. Molecular interventions, v. 1, n. 1, p. 30– 8, abr. 2001.
MIATELLO, R. et al. Aortic smooth muscle cell proliferation and endothelial nitric oxide synthase activity in fructose-fed rats. American journal of hypertension, v. 14, n. 11 Pt 1, p. 1135–41, nov. 2001.
the arterial wall. An explanation for the anti-thrombotic properties of vascular endothelium. Thrombosis Research, v. 11, n. 3, p. 323–344, 1977.
MONCADA, S.; PALMER, R. M.; HIGGS, E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacological reviews, v. 43, n. 2, p. 109– 42, jun. 1991.
MONTEZANO, A. C.; TOUYZ, R. M. Reactive Oxygen Species and Endothelial Function - Role of Nitric Oxide Synthase Uncoupling and Nox Family Nicotinamide Adenine Dinucleotide Phosphate Oxidases. Basic & Clinical Pharmacology & Toxicology, v. 110, n. 1, p. 87–94, jan. 2012.
MORENO, J. A.; HONG, E. A single oral dose of fructose induces some features of metabolic syndrome in rats: role of oxidative stress. Nutrition, metabolism, and cardiovascular diseases : NMCD, v. 23, n. 6, p. 536–42, jun. 2013.
MORITA, I. Distinct functions of COX-1 and COX-2. Prostaglandins & other lipid mediators, v. 68–69, p. 165–75, ago. 2002.
MOZAFFARIAN, D. et al. AHA Statistical Update Heart Disease and Stroke Statistics — 2016 Update A Report From the American Heart Association WRITING GROUP MEMBERS. [s.l: s.n.].
MURPHY, M. P. How mitochondria produce reactive oxygen species. Biochemical Journal, v. 417, n. 1, p. 1–13, 1 jan. 2009.
MURRAY, R. K. et al. Bioquímica ilustrada de Harper (Lange). 29. ed. [s.l.] AMGH, 2013.
NAKAGAWA, T. et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol, v. 290, p. 625–631, 2006.
NYBY, M. D. et al. Vascular Angiotensin Type 1 Receptor Expression Is Associated with Vascular Dysfunction, Oxidative Stress and Inflammation in Fructose-Fed Rats. Hypertension Research, v. 30, n. 5, p. 451–457, maio 2007.
OUYANG, X. et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. Journal of Hepatology, v. 48, n. 6, p. 993–999, jun. 2008.
Oxidative Phosphorylation - Biology - OpenStax CNX. Disponível em: <http://cnx.org/contents/[email protected]:7oTVAgrZ@7/Oxidative-Phosphorylation>.
Acesso em: 27 fev. 2017.
PALMER, R. M.; ASHTON, D. S.; MONCADA, S. Vascular endothelial cells synthesize nitric oxide from L-arginine.Nature, 1988.
PANTH, N.; PAUDEL, K. R.; PARAJULI, K. Reactive Oxygen Species: A Key Hallmark of Cardiovascular Disease. Advances in medicine, v. 2016, p. 9152732, 2016. PARKS, E. J. et al. Dietary Sugars Stimulate Fatty Acid Synthesis in Adults 1–3. The Journal of nutrition, n. February, p. 1039–1046, 2008.
PEREDO, H. A. et al. Oral treatment and in vitro incubation with fructose modify vascular prostanoid production in the rat. Autonomic and Autacoid Pharmacology, v. 26, n. 1, p. 15–20, jan. 2006.
PETERSEN, K. F. et al. Stimulating effects of low-dose fructose on insulin-stimulated hepatic glycogen synthesis in humans. Diabetes, v. 50, n. 6, p. 1263–8, jun. 2001. PRESTON, G. M.; CALLE, R. A. Elevated Serum Sorbitol and not Fructose in Type 2 Diabetic Patients. Biomarker insights, v. 5, p. 33–8, 4 maio 2010.
PRIETO, P. G. et al. Plasma D-glucose, D-fructose and insulin responses after oral administration of D-glucose, D-fructose and sucrose to normal rats. Journal of the American College of Nutrition, v. 23, n. 5, p. 414–9, out. 2004.
PUYÓ, A. M. et al. Time course of vascular prostanoid production in the fructose- hypertensive rat. Autonomic and Autacoid Pharmacology, v. 29, n. 3, p. 135–139, 2009.
RICHEY, J. M. et al. FRUCTOSE PERFUSION IN RAT MESENTERIC ARTERIES IMPAIRS ENDOTHELIUM-DEPENDENT VASODILATION. Life Sciences, v. 62, n. 4, p. PL55-PL62, 1997.
RINCÓN, J. et al. Role of Angiotensin II type 1 receptor on renal NAD(P)H oxidase, oxidative stress and inflammation in nitric oxide inhibition induced-hypertension. Life sciences, v. 124, p. 81–90, 1 mar. 2015.
ROMANKO, O. P. et al. Insulin Resistance Impairs Endothelial Function but not Adrenergic Reactivity or Vascular Structure in Fructose-fed Rats. p. 414–423, 2009. RUBANYI, G. M.; VANHOUTTE, P. M. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. The American journal of physiology, v. 250, n.
5 Pt 2, p. H822-7, maio 1986.
SATOH, K. et al. Dual roles of vascular-derived reactive oxygen species—With a special reference to hydrogen peroxide and cyclophilin A—. Journal of Molecular and Cellular Cardiology, v. 73, p. 50–56, ago. 2014.
SCHAEFER, E. J.; GLEASON, J. A.; DANSINGER, M. L. Dietary Fructose and Glucose Differentially Affect Lipid and Glucose Homeostasis. Journal of Nutrition, v. 139, n. 6, p. 1257S–1262S, 1 jun. 2009.
SEMCHYSHYN, H. M. Fructation in vivo: Detrimental and protective effects of fructoseBioMed Research International, 2013.
SHULMAN, G. I. Cellular mechanisms of insulin resistance. Journal of Clinical Investigation, v. 106, n. 2, p. 171–176, 15 jul. 2000.
SKEGGS, L. T. et al. The purification of hypertensin I. The Journal of experimental medicine, v. 100, n. 4, p. 363–70, 1 out. 1954.
SLYPER, A. H. The influence of carbohydrate quality on cardiovascular disease, the metabolic syndrome, type 2 diabetes, and obesity - an overview. Journal of pediatric endocrinology & metabolism : JPEM, v. 26, n. 7–8, p. 617–29, 1 jan. 2013.
SUN, S. Z.; EMPIE, M. W. Fructose metabolism in humans - what isotopic tracer studies tell us. Nutrition & metabolism, v. 9, n. 1, p. 89, 2 out. 2012.
SWARBRICK, M. M. et al. Consumption of fructose-sweetened beverages for 10 weeks increases postprandial triacylglycerol and apolipoprotein-B concentrations in overweight and obese women. The British journal of nutrition, v. 100, n. 5, p. 947– 52, 2008.
TAKAGAWA, Y. et al. Long-term fructose feeding impairs vascular relaxation in rat mesenteric arteries. American journal of hypertension, v. 14, n. 8 Pt 1, p. 811–7, ago. 2001.
TANG, E. H. C.; VANHOUTTE, P. M. Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension. Physiological Genomics, v. 32, n. 3, p. 409– 418, 6 nov. 2007.
postprandial suppression of ghrelin, and increases triglycerides in women. The Journal of clinical endocrinology and metabolism, v. 89, n. 6, p. 2963–72, jun. 2004.
TEFF, K. L. et al. Endocrine and metabolic effects of consuming fructose- and glucose- sweetened beverages with meals in obese men and women: Influence of insulin resistance on plasma triglyceride responses. Journal of Clinical Endocrinology and Metabolism, v. 94, n. 5, p. 1562–1569, 2009.
THORENS, B.; MUECKLER, M. Glucose transporters in the 21st Century. AJP: Endocrinology and Metabolism, v. 298, n. 2, p. E141–E145, 1 fev. 2010.
TURNER, J. L. et al. Effect of dietary fructose on triglyceride transport and glucoregulatory hormones in hypertriglyceridemic men. American Journal of Clinical Nutrition, v. 32, n. 5, p. 1043–1050, 1979.
VARTANIAN, L. R.; SCHWARTZ, M. B.; BROWNELL, K. D. Effects of soft drink consumption on nutrition and health: a systematic review and meta-analysis. American journal of public health, v. 97, n. 4, p. 667–75, abr. 2007.
WAHJUDI, P. N. et al. Measurement of glucose and fructose in clinical samples using gas chromatography/mass spectrometry. Clinical biochemistry, v. 43, n. 1–2, p. 198– 207, jan. 2010.
WATTANAPITAYAKUL, S. K.; BAUER, J. A. Oxidative pathways in cardiovascular disease: roles, mechanisms, and therapeutic implications. Pharmacology & therapeutics, v. 89, n. 2, p. 187–206, fev. 2001.
WHITE, J. S. Challenging the Fructose Hypothesis: New Perspectives on Fructose Consumption and Metabolism. Advances in Nutrition: An International Review Journal, v. 4, n. 2, p. 246–256, 1 mar. 2013.
YANAGISAWA, M. et al. A novel peptide vasoconstrictor, endothelin, is produced by vascular endothelium and modulates smooth muscle Ca2+ channels. Journal of hypertension. Supplement : official journal of the International Society of Hypertension, v. 6, n. 4, p. S188-91, dez. 1988.